Vascular prostheses and implants in the form of stents are known from the state of the art to a large extent. Essentially a distinction is to be made between balloon-expanding or self-expanding stents, which, by means of an insertion device, such as for instance a catheter, are inserted into a body lumen. Common to all stents is that, for insertion into a body lumen, they must have a more minimal diameter than in the exercising of their function in the body. As a rule, the stents are delivered and packaged in a compressed state under so-called cleanroom conditions. A cleanroom is a room in which the concentration of particle is continuously monitored. Cleanrooms are categorized in various classes, so-called ISO classes; thus e.g. in a cleanroom of the class ISO-7, the number particles that are 0.5 micrometer in size may not be more than 352 000 per cubic meter. For 1.0 micrometer the upper limit is 83 200 and for 5.0 micrometer 2930 particles per cubic meter (according to DIN EN ISO 14644). Particles smaller than 0.5 micrometer are not taken into consideration in this class. Such an ISO-7 cleanroom is often used for medical implants, such as e.g. stents.
A cleanroom for producing and preparing stents on catheters is thus not 100% free of particles. Moreover, in particular for stents and catheter many production steps are carried out manually. Since, as a rule, the human being is the greatest source for particles and other contamination, a suitable packaging helps to keep the specified cleanroom class.
The stents implanted in blood vessels entail certain risks for the patient. Among other things, inflammatory reactions and/or development of thrombosis on the structures of the stent lead to a renewed stenosis in the blood vessels. Complications of this kind are caused inter alia by soiling of the stent, i.e. its surface, the implant device or other elements that come into contact with the stent, during insertion of the stent into the body lumen. The stent and the insertion device should therefore be as free as possible of any contamination, i.e., for example, have no dust, no fibers, chemical impurities (such e.g. hydrocarbon compounds, residue from electropolishing processes, etc.) or particles in general.
Such contamination can arise with conventional methods for preparation of a stent for implantation e.g. also after a surface treatment and cleaning of the stent, during crimping or insertion on or in a catheter. For example, “naturally” occurring contamination, caused by work carried out in the cleanroom e.g. by work gloves or diverse particles from the atmosphere, can remain adhered to the stent. By means of optical controls after stent mounting on the catheter any particles can be noticed and, if need be, be removed using a clean gas (e.g. oil-free and particle-free, ionized air) flowing out of a nozzle.
The success of the treatment of a body lumen, such as e.g. a coronary artery, using a stent is consequently significantly dependent on the surface characteristics of the stent. Known from US 2008/0086198 A1 is a stent with a nanoporous surface layer, which should improve the ingrowth of the stent and its re-endothelialization and reduce inflammation and an intimal proliferation. The nanoporous surface layer with one or more therapeutic active substances can thereby be provided in order to improve further the described functions of the stent. There are numerous examples of active substance layers, inter alia hydrophilic or hydrophobic active substance layers are generated on the stent surface. Furthermore, shown in FIGS. 24 to 26 are experimental results for stents with a controllable elution system, which has a more minimal restenosis compared with stents with bare metal surface (bare metal stents). The reduced degree of restenosis with a stent with nanoporous surface is attributed to an improved biocompatibility and an improved complete healing of the body tissue. In contrast thereto, with simple metal surface, a chronic irritation of the tissue surrounding the Stent is presumed. No conclusive studies have been made concerning the purity of the stent surface.
Soehnlein et al. (Neutrophil-Derived Cathelicidin Protects from Neointimal Hyperplasia; Sci Transl Med 3, 2011) shows a stent having a protein coating with the protein cathelicidin (LL37). The ingrowth behavior of the coated stents was tested in trials on animals. The trials showed a more minimal restenosis, and it is suspected that cathelicidin promotes and regulates the Re-endothelialization, and thereby protects against a neointimal hyperplasia following the stent implantation. The use of coatings on stents generally has drawbacks however. For example, the surface friction of the stent can be increased; the coating can be damaged with expansion of the stent (tearing, bursting, etc.) or can bring about negative side effects involving blood circulation.
Known from EP 0606566 B1 is a method for producing implant surfaces in which the surfaces of the implant are plasma-treated. With plasma treatment, contamination layers, such as for instance hydrocarbons and other particles deposited from the environment can be removed. The preparation of the stent thus takes place in a chamber with cleanroom conditions.
Although the stent surface can namely be cleaned with a cleaning process in the said methods, the purity of the stent surface thereby corresponds at best to the cleanliness classes of the cleanrooms applied. A higher cleanliness with lesser contamination than corresponding to this cleanliness class cannot be achieved with these methods.
For characterization of the metal surface of implants, various measuring methods are known, such as for example the measurement of the electrophoretic mobility, the measurement of the surface charge by means of acid base titration, the impedance spectrometry, voltametry or electron microscopy (REM). By means of REM analysis, e.g. the roughness or grain size of a polished metal stent surface can be viewed. The wetting characteristics of the implant surface can be determined by measuring the angle of contact between liquid and dry metallic surfaces by means of optical methods. Contact angle measurements of this kind are carried out, for example, by application of small drops on one or more selected places of a surface to be measured and subsequent optical recording of the wetting behavior of the surface. However only a punctual examination of the wetting features can thereby take place. It is not possible to analyze the entire surface.
These known methods for examination of the surface characteristics are either very complicated and costly, or can capture only a small portion of the surface or are unsuitable for complex geometries, such as with a stent, and thus do not allow any examination and characterization of the entire surface of a stent. Furthermore extremely small particles, such as carbon contaminants from the environment, below a certain degree of contamination, can hardly be registered.
Known from material analysis are analytical methods having a higher precision than the above-mentioned methods. Used for characterization of the surfaces is thereby X-ray photoelectron spectroscopy (XPS), the energy-dispersive X-ray spectroscopy or a mass spectroscopy method (e.g. Time-of-flight Secondary Ion Mass Spectroscopy Method (TOF-SIMS)). These methods are hardly suited for simple determination of the purity of a stent surface, however. In particular they are not advantageous for detection of contaminants, which e.g. consist of hydrocarbon compounds, for distinguishing between stents prior to and subsequent to a cleaning, and, if necessary after further manipulative steps. For carrying out analyses of this kind, the stents must be prepared according to analysis requirements, whereby a contamination of the stent surface can take place within the range of contamination to be measured. Furthermore it is hardly possible to create an analysis room that itself does not contribute to contamination of the stent surface. Moreover methods of this kind are very complicated and costly.